Case Description

The urine of a 36-year-old man tested positive for paliperidone (9-hydroxyrisperidone). The patient denied having taken risperidone or paliperidone, 2 drugs that can cause positivity for paliperidone.

This patient was diagnosed with schizoaffective disorder and is currently prescribed antipsychotic and other mental health-related medications: clomipramine (25/75 mg) and clozapine (200 mg), both at bedtime. Urine specimens were collected to monitor medication adherence. Quantitative LC-MS/MS methods developed and validated in our laboratory were used to test for various antipsychotic drugs and related metabolites in urine. Laboratory results included clomipramine, 264 ng/mL; clozapine, 990 ng/mL; n-desmethylclozapine, 4178 g/L; and paliperidone, 12 ng/mL, by LC-MS/MS. Reporting cutoffs for these medications are 200 ng/mL, 25 ng/mL, 25 ng/mL, and 5 ng/mL, respectively. Sample validity testing results included specific gravity, 1.009; pH 5.3; and creatinine, 99.1 g/L, which are all acceptable within range.

n-Desmethylclozapine is a metabolite of clozapine, and its positive result matched with the prescription for clozapine. However, the paliperidone result could be from either the parent drug (such as Invega®) or as a metabolite of risperidone (Risperdal®) use. Neither of these drugs was listed as a current prescription for the patient. A technical replicate of the urine using the same LC-MS/MS method reconfirmed the presence of paliperidone.

Discussion

It is reported that patients with serious mental diseases (such as schizophrenia) may have increased risk of nonadherence to prescribed antipsychotic medications, which can lead to negative clinical outcomes (1, 2). Urine drug testing is an effective way to monitor the likelihood of medication adherence for these patients. Risperidone is an antipsychotic medication used to treat patients with schizophrenia or bipolar disorder. In vivo, risperidone is primarily metabolized by cytochrome P450 enzyme CYP2D6 to an active metabolite, 9-hydroxyrisperidone/paliperidone (3), and its half-life is 3 h and 20 h in CYP2D6-extensive metabolizers and -poor metabolizers, respectively (4). Paliperidone (Invega®) is also a second-generation antipsychotic for the management of schizophrenia. Clinical studies indicate that the metabolism of paliperidone is limited and most of it is excreted unchanged in the urine; there are no significant differences observed between CYP2D6-poor and -extensive metabolizers (5–7).

To determine whether this was an isolated case, the results of all urine specimens that tested positive for paliperidone over the past 4 years (2013–2016) were collected and reviewed. In total, 31 samples from 6 patients were found with positive results for paliperidone in the absence of a prescription for risperidone or paliperidone. Of the 31 positive samples, records indicate that we sent 3 to an outside laboratory and the same paliperidone-positive results were obtained. It is worth noting that all 6 patients were overweight with a body mass index of >30. Two of the patients had urine testing history for >1 year in our database, and therefore, we could retrospectively analyze the paliperidone concentration changes during that time. Patient A was tested every month to monitor adherence to medications. Data indicated that this patient had tested low positive for paliperidone for 16 months (Fig. 1A) in a decreasing trend. Interestingly, paliperidone was not observed in the 13th month but it was positive again in the 14th and 15th months. Patient B had 3 years of urine testing history in our database. Notably, this patient was prescribed Invega once, which was then replaced with Haldol® (haloperidol). Data indicated that the patient tested negative for paliperidone before being prescribed Invega (Fig. 1B, first 2 points) and tested positive for paliperidone after being prescribed Invega (Fig. 1B, indicated by arrow). Although Invega was stopped and replaced with Haldol after the 4th month, paliperidone was continuously positive for >3 years with a decreasing trend. Negative paliperidone results were also observed twice at the 36th and 43rd months and then positive again in the following specimens.

Fig. 1.Paliperidone has been continuously detected for >1 year in 2 patients (A and B) without medications.

Palip, paliperidone; Palip/Crt, ratio of paliperidone to creatinine; arrow in B, testing time when patient was prescribed Invega®.

It is hypothesized that, particularly for these 2 cases, the consistent low positive results for paliperidone so long after the paliperidone therapy was stopped could be because of the storage of paliperidone in fat tissues, as these patients were clinically obese (body mass index >30), and because paliperidone is sparingly soluble in water (8) and therefore favors a lipid environment. The random and intermittent negative results among the positive trend for these patients could be because of several reasons. In particular, the hydration status of the patient at the time of urine collection could affect the paliperidone concentration, resulting in a value just below the reporting cutoff of 5 ng/mL. In addition, whether there was recent exercise or a lack thereof could affect the concentration if paliperidone is in fact being sequestered in the fat of these patients.

Based on these data, further communication with the clinician confirmed that the patient in this case had a paliperidone prescription (Invega Sustenna®, 234 mg intramuscular every 4 weeks) 16 months ago.

In addition to the aforementioned 6 patients with 31 positive paliperidone results without medications, we also found 6115 patients with 7416 positive urine paliperidone results consistent with their prescription(s). Among them, 4946 (67%) were from patients with a prescription containing risperidone, and 2740 (33%) were from patients with a prescription containing paliperidone. Urine paliperidone concentrations (median and range) are shown based on the administration routes (oral, intramuscular) in Table 1. Because of the large biological variations that exist in urine samples (such as hydration state, sample volume, and rate of urine production), the paliperidone concentrations were also “normalized” to patient creatinine concentrations (shown as ratio of paliperidone to creatinine) (Table 1).

Urine concentrations for paliperidone based on medication and administration routes.a

Data in Table 1 indicate that median values of paliperidone urine concentrations are higher in those in whom the drug was administered through muscular injection than those through oral administration routes. Concentrations from patients who were prescribed paliperidone are higher than those prescribed risperidone. However, paliperidone urine concentrations from different drug formulations or different administered routes can span a large range, from 5 ng/mL (lower limit of quantification) to >10000 ng/mL (Table 1). Therefore, it is difficult to correlate the paliperidone urine concentrations to the parent drug or the administered routes. The variation of urine concentration could be because of the last dosage time, individual differences in pharmacokinetics, or patient status when the urine samples were collected. Interestingly, the median value of the 31 patients with medication-inconsistent urine paliperidone concentrations is far lower than those from patients prescribed the medications, and in a smaller range of 5–157 ng/mL. Similar results were also observed for the “normalized” concentrations (Table 1), implying that low concentrations of paliperidone could be, as hypothesized, caused by the residual drug in the body even after therapy has ceased. However, as discussed above, urine paliperidone concentration could be as low as 5 ng/mL for patients who are taking the medications. Therefore, clinicians cannot draw a conclusion concerning patient adherence based solely on the low paliperidone result. Instead, clinicians should carefully review a patient's medication history, particularly those who are overweight and have low positive urine testing results for paliperidone as far back as 3 years before the test date to rule out true nonadherence to prescriptions as opposed to some other biologically related explanation. It is possible that these results are unique to paliperidone; however, other antipsychotic drugs remain to be examined.

TAKEAWAYS

Both risperidone and paliperidone are antipsychotic medications used to treat patients with schizophrenia or bipolar disorder. In the human body, paliperidone could be from either the metabolite of risperidone or the parent drug itself.

Paliperidone can potentially stay in the body, particularly in overweight patients, for >3 years even after therapy has ceased.

Physicians should carefully ask for medication history, even as far back as 3 years ago, to rule out nonadherence to prescriptions, particularly for patients with low positive results.